The objective of this Program Project is to provide new insight into the relationship between fatty acids and cardiovascular disease, with emphasis on mechanisms involved in hyperlipidemia and atherosclerosis. Our goals are to determine how polyunsaturated fatty acids (PUFA) affect lipoprotein production and removal mechanisms, how postprandial lipoproteins enriched in omega-3 PUFA influence vascular prostanoid formation, and how tissue PUFA content and composition relates to lipid peroxidation and oxidized lipoproteins. The Program consists of four research projects and two core units. Project 1 (Spector) deals with the role of PUFA in cell function, with emphasis on lipid peroxidation and the detection of lipid radicals in intact cells. Project 2 (Field) concerns the role of fatty acids in intestinal lipoprotein formation, including the relationship between intestinal lipoprotein formation, including the relationship between intestinal processing of cholesterol and the regulation of apolipoprotein B formation. Project 3 (Chappell) will characterize the properties of postprandial lipoproteins formed in response to acute and chronic omega-6 PUFA ingestion, as well as the effect of enrichment with these PUFA on lipoprotein binding to receptors and catabolism. Project 4 (Knapp) deals with the effects of ingestion of marine oils, the role of postprandial lipoproteins containing omega-3 PUFA on eicosanoid production at the vascular interface, and the effect of fatty acid oxidation products in the bile on chylomicron formation. These projects are supported by a Cell Culture Core (Spector) and an Administrative Core (Spector). Among the novel features of this program is the interplay between human investigation and the use of cell culture models, the application of electron paramagnetic resonance and spin traps to detect lipid radicals in intact cells, and the development of mass spectrometry methods to measure eicosanoid formation and oxidized lipid products in clinical studies. The findings will increase our understanding of the mechanisms through which PUFA exert their protective effects against cardiovascular diseases.